Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure Renewal

小儿脓毒症引起的多器官衰竭更新的炎症表型

• 批准号: 10017690
• 负责人: JOSEPH A CARCILLO
• 金额: $ 50.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017690
• 关键词: Accident and Emergency department; Address; Adenoviruses; Adult; American; Anti-Inflammatory Agents; Antibiotics; Big Data; Bioinformatics; Cessation of life; Child; Childhood; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Coagulation Process; Complement; Computers; Cytomegalovirus; DNA; DNA Viruses; Data; Depressed mood; Development; Excision; Funding; Future; Genes; Germ; Hemorrhage; Herpesvirus 1; Home environment; Human Genetics; Human Herpesvirus 4; Human Herpesvirus 6; IV Fluid; Immune; Immunity; Incidence; Individual; Infection; Inflammation; Intensive Care Units; Interleukin-1; Interleukin-18; Interleukin-6; Kidney Failure; Knowledge; Liver Failure; Machine Learning; Macrophage activation syndrome; Mendelian disorder; Methods; Modeling; Molecular Biology; Monoclonal Antibodies; Multiple Organ Failure; National Institute of General Medical Sciences; Natural Immunity; Organ; Pathogenicity; Patients; Pediatric Intensive Care Units; Phenotype; Plasma; Plasma Exchange; Precision medicine trial; Proteins; Research Personnel; Risk; Sampling; Sepsis; Septic Shock; Specific qualifier value; Syndrome; Technology; Testing; Thrombocytopenia; Time; United States National Institutes of Health; Variant; Viremia; Virus; Virus Diseases; adaptive immunity; base; clinical biomarkers; co-infection; cohort; cytokine; design; exome; fighting; gene interaction; genetic analysis; individual patient; individualized medicine; mortality; mortality risk; novel; precision medicine; recruit; science education; septic patients; targeted treatment; trial design; virus genetics

Carcillo R01 Project Abstract Every year over 1 million American adults and children develop overwhelming infection leading to a rotting of their body we call ‘sepsis’, and death in up to 1 of 3 afflicted (www.nigms.nih.gov>NIGMS Home>Science Education). National efforts emphasizing early recognition, intravenous fluids to help organs, and antibiotics to kill infection, have reduced mortality so that now 1 of 4 die. We and others have asked the question “why do patients continue to die despite these national efforts?’ In the previous funding period we showed in 401 children with sepsis that those who developed organ shut down despite these efforts, did so because they were a) unable to fight germs causing unending infection, b) unable to stop clotting off their body causing kidney failure, and/or c) unable to kill viruses causing liver failure; all of which led to death from uncontrolled inflammation with clotting, bleeding and liver failure. Fortunately, each of these organ shutdown groups has hopeful treatments. With the new information we collected in the previous funding period we have already designed and started clinical trials testing these treatments including immune boosters for children unable to kill germs, plasma removal and replacement using plasma exchange for children unable to stop clotting, monoclonal antibodies to kill viruses and their homes to reverse liver failure in children unable to do so on their own, and anti-inflammatory proteins to reverse uncontrollable inflammation, in hopes of helping save many of the 1 of 4 children still dying from sepsis related organ shutdown. In this next funding period, we propose to use the clinical information and samples already obtained in our previous study to take advantage of the wonderful advances made this millenia in computer technology, big data, bioinformatics, and the study of human and virus genetics to perform Specific Aim 1) use a ‘Watson’ like approach to ask the computer to help us figure out if the children with sepsis have any other causes of organ shutdown that we can help, Specific Aim 2) use an ‘Ancestry.com’-like or ‘23 and me’-like approach to identify ‘precision medicine’ therapies for causes of organ shutdown that we can treat on a patient by patient basis, and Specific Aim 3) use a bedside molecular biology test approach to identify individualized therapies to kill DNA viruses and reduce cytokine inflammation. We think that DNA viruses are the unappreciated co-infection which causes uncontrolled cytokine inflammation and leads to organ shutdown. Our long term objective is to plan ‘precision’ medicine and ‘individualized’ medicine clinical trials testing therapies on an individual patient basis in order to further reduce death from sepsis organ shutdown in children.

Carcillo R01 项目摘要 每年有超过 100 万美国成人和儿童出现严重感染，导致 导致他们的身体腐烂，我们称之为“败血症”，并且多达三分之一的患者死亡 （www.nigms.nih.gov>NIGMS Home>科学教育）。 认识、静脉输液帮助器官以及抗生素杀死感染，已经减少了 死亡率，现在 4 人中有 1 人死亡，我们和其他人提出了这样一个问题：“为什么患者会死亡”。 尽管国家做出了这些努力，但仍然继续死亡？”在之前的资助期间，我们展示了 401 名患有败血症的儿童，尽管做出了这些努力，但那些出现器官关闭的儿童还是这样做了 因为他们a）无法对抗导致无休止感染的细菌，b）无法阻止 身体凝结导致肾衰竭，和/或 c) 无法杀死导致肝衰竭的病毒； 所有这些都导致患者因不受控制的炎症、凝血、出血和肝功能衰竭而死亡。 幸运的是，这些器官关闭组中的每一个都通过新的治疗方法获得了希望。 我们在上一个资助期间收集的信息我们已经设计并开始 测试这些治疗方法的临床试验，包括针对无法杀死儿童的免疫增强剂 使用血浆交换为无法停止的儿童去除细菌、血浆 凝血、杀死病毒的单克隆抗体及其逆转儿童肝衰竭的家园 无法自行做到这一点，而抗炎蛋白则无法控制地逆转 炎症，希望能够帮助拯救仍然死于败血症相关的 4 名儿童中的 1 名 在下一个资助期内，我们建议使用临床信息和 利用我们之前研究中已经获得的样本来利用这些惊人的进步 在计算机技术、大数据、生物信息学以及人类和人类研究方面创造了这一千年 病毒遗传学来执行特定目标 1）使用类似“沃森”的方法来要求计算机 帮助我们弄清楚患有败血症的儿童是否还有我们所知道的任何其他导致器官功能衰竭的原因 可以提供帮助，具体目标 2) 使用类似“Ancestry.com”或“23 和我”的方法来识别 针对器官关闭原因的“精准医学”疗法，我们可以通过以下方式对患者进行治疗： 患者基础和具体目标 3) 使用床边分子生物学测试方法来识别 我们认为，个体化疗法可以杀死 DNA 病毒并减少细胞因子炎症。 DNA 病毒是一种未被重视的混合感染，会导致细胞因子失控 我们的长期目标是“精确”计划。 医学和“个体化”医学临床试验，测试针对个体患者的治疗方法 为进一步减少儿童因败血症器官关闭而死亡的基础。